CA1066268A - Process for preparing 3-acyloxymethyl-2-cephem compounds - Google Patents

Abstract

Abstract of the Disclosure The present invention relates to a novel process whereby a 3-exomethylenecepham sulfoxide ester is reacted with a mixture of a C1-C4 carboxylic acid and a corresponding C1-C4 acid anhydride at a temperature of from about 70°C. to about 130°C. to produce the corresponding 3-acyloxymethyl-.DELTA.2-cephem, which is useful as an intermediate in the preparation of antibiotically active cephalosporins.

Description

~1~66216 8 The present invention relate~ to a no~el p~ocess whereby a 3-exomethylenecepha~ sulfoxide e$ter is xeacted with a mixture of a Cl-C4 carboxylic acid and a corresponding Cl-C4 acid anhydride at a temperature of ~rom about 70C. to about 130C. to produce the corresponding 3-acyloxymethyl _ ~2 _ ce-phem, which is use~ul as an intermediate in the preparation of antibiotically active cephalosporins.
Cephalosporin antibiotics having an acyloxymethyl group at the C3 carbon atom of the cephem nucleus are well re-cognized in the cephalosporin art, see, for example, United States Patents Nos. 3,270,009; 3,278,531; 3,532,694; 3,705,897;
3,728,342; and 3,795,672. New methods for preparing these cephalosporins cGntinually are being sought. This invention is directed to a process for preparing 3-acyloxymethyl- ~2 _ cephem compounds, which compounds are readily convertlble by recognized techniques to the aforementioned 3-acyloxymethyl ce-phalosporin antibiotics.
Recently, 3-exomethylenecepham esters have been de-scribed, for example, in Chauvette et al., J. Org. Chem., 38 2994 (1973); and in U.S. Patent No. 3,792,995. These compounds have the general formula ... .. .

R

C~2 COORl ~, ,~ .. .

-2- ~

.: .: ' ' ,, ,' ' :

~06626~
m e corresponding sulfoxides o~ Formula II below are starting materials employed in the process of this invention and are readily available from the corresponding 3-exomethylene-cepham esters by known methods. For example, a 3-exomethyl- ~
enecepham acid or ester can be reacted with a peracid, for -example, m-chIoroperbenzoic acid, perbenzoic acid, peracetic adid, and the like, to form the corresponding sulfoxide.
m e 3-exo double bond of the starting material is inert under these conditions of sulfoxide formation, and, con-sequently, the sulfoxide is prepared by the selective oxidation of the sulfide.
m e sulfoxide ester starting materials are preferably prepared by reacting a penicillanic acid ester sulfoxide with an N-chloro halogenating agent in a dry, inert organic solvent at a temperature between 70C. and about 100C. to provide an azetidinone sulfinyl chloride. m e sulfinyl chloride then is reacted with a Lewis acid Friedel-Crafts type catalyst in a dry, inert, organic solvent to effect cyclization and to provide the 3-exomethylenecepham sulfoxide ester.
As indicated, the 3-exomethylenecepham sulfoxide esters represent the starting materials of the process of this invention, and it has now been discovered that it is possible to convert these sulfoxide esters to their corresponding

3-acyloxymethyl- ~2-cephems, which class of com-"~

':. :. ,. . ., ' , ,~ . ,.
., :, . ' , ;6~;8 pounds is useful as intermediates in the preparation of theaforementioned 3-acyloxymethyl cephalosporins (3-acyloxy-methyl-~3-cephem compounds).
This invention is directed to a novel process for preparing a compound of the formula :

l I

which comprises reacting a 3-exomethylenecepham sulfoxide of the formula O . ,' OORl :

, '' :
; .:: ~: '~ ' ' : .

,:' . :, ' " ' ~ ' '~ ' ' . , ' . ' ., , , :

~066~68 with a mixture of an acyl compound of the formula O

and a corresponding anhydride of the formula O
(R~-C-)2O IV
at a temperature of from about 70C. to about 130C., in which, in the above formulae, R~ is Cl-C4 alkyl, Rl is a carboxylic acid protecting group, and R is (1) an imido group of the formula = ~

in which R2 is C2-C4 alkenylene or 1,2-phenylene; ;

- (2) an amido group of the formula O

in which R3 is -(a) hydrogen, Cl-C3 alkyl, halomethyl, benzyloxy, ; .

4-nitrobenzyloxy, 2,2,2-trichloroekhoxy, 4-methoxybenæyloxy, ~ ~ :
3-(2-chlorophenyl)-5-methylisoxaæol-4-yl;
(b) the group R' in which ~' is phenyl or phenyl .
substituted with l or 2 halogens, nltro, cyano, trifluo.ro-methyl, Cl-C~ alkyl, or Cl-C4 alkoxy;
(c) a group of the formula R'-(O)m-CH2- in which R' is as defined above and m is 0 or 1;

X-~560 -5- .
. .
' .
~,: ' - , ~066'~:G8 (d) a group of the formula R''-CH- in which COORl R" is R' as defined above, 2-thienyl, or 3 thienyl, and R
is as defined above; or (e) a group of the formula R'''-CH2- in which R''' is 2~thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-thiazolyl,

5-tetrazolyl, l-tetrazolyl, or 4-isoxazolyl; or R is (3) an imidazolidinyl group of the formula ".

R'~ /~

~N~----t--CH3 U ~H3 . . :
in which R' is as defined above and U is nitroso or acetyl. ;~
Rl in the above formulae I and II denotes a car-boxylic acid protecting group, and, preferably, one which is removable by hydrogenation. Preferred carboxylic acid protecting groups include, for example, 2,2,2-trihaloethyl, benzyl, p-nitrobenzyl, succinimidomethyl, phthalimidomethyl, ~ :
p-methoxybenzyl, C2-C6 alkanoyloxymethyl, dimethylallyl, 20 phenacyl, or p-halophenacyl, in any of the above o~ which ::
halo denotes chlorine, bromine or iodine. :~ .
Specific illustrations of the preferred carboxylic : :
acid protecting groups include, for example, 2,2,2-tri-chloroethyl, 2,2,2-tribromoethyl, benzyl, p-nitrobenzyl, ::~
succinimidomethyl, phthalimidomethyl, ~-methoxybenzyl, acetoxymethyl, pivaloyloxymethyl, propionoxymethyl, phen- ~:
acyl, ~-chlorophenacyl and ~-bromophenacyl. ~:
Highly preferred carboxylic acid protecting groups - ~ .
are benzyl, _-nitrobenzyl, ~-methoxybenzyl, 2,2,2-trichloro-ethyl, phenacyl, _-chlorophenacyl, and p-bromophenacyl.
X-4560 -6- :

, , . . , , , , , :

~36626~3 Most preferred carboxylic acid protecting groups are p-nitrobenzyl and 2,2,2-trichloroethyl.
The group R in the 7-position of the 3-exomethyl-enecepham sulfoxide starting materials of Formula II and the 3-acyloxymethyl-A2-cephem products of Formula I is, in part, , . . .
defined as R3-C-NH-.
Specific illustrations of the group R3 include, for example, hydrogen, methyl, ethyl, _-propyl, isopropyl, chloromethyl, bromomethyl, benzyloxy, 4-nitrobenzyloxy, 2,2,2-trichloroethoxy, 4-methoxybenzyloxy, phenyl, 2-chlorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, :~
4-nitrophenyl, 2-cyanophenyl, 4-trifluoromethylphenyl, 3-methylphenyl, 2-ethylphenyl, 4-n-propylphenyl, 4-_-butyl-phenyl, 2~methoxyphenyl, 4-ethoxyphenyl, 3-isopropyloxy-. -~
phenyl, 4-isobutyloxyphenyl, benzyl, 3-bromobenzyl, 2,5-dichlorobenzyl, 4-chloroacetoxybenzyl, 2-nitrobenzyl, 3-cyanobenzyl, 4-trifluoromethylbenzyl, 3-methylbenzyl, 4-n-butylbenzyl, 2-methoxyben~yl, 3-isopropoxybenzyl, . .
phenoxymethyl, 3-iodophenoxymethyl, 4-fluorophenoxymethyl, 3-chloro-4-fluorophenoxymethyl, 2,5-dichlorophenoxymethyl, 3-isopropoxyphenoxymethyl, 4-ethylphenoxymethyl, 4-chloro-phenoxymethyl, 3-nitrophenoxymethyl, 4-cyanophenoxymethyl, 2-trifluoromethylphenoxymethyl, 3-methylphenoxymethyl, 4-_-propylphenoxymethyl, 4-_-butylphenoxymethyl, 3-methoxy-phenoxymethyl, 4-ethoxyphenoxymethyl, a-(benzyloxycarbonyl)- - , thien-2-ylmethyl, a-(4-nitrobenzyloxycarbonyl)-thlen-2- :
ylmethyl, a-(4-methoxybenzyloxycarbonyl)-thien-2-ylmethyl, a-(phenacyloxycarbonyl)-thien-3-ylmethyl, a-(4-nitrobenzyl ~ -oxycarbonyl)-thien-3-ylmethyl, a-(benzyloxycarbonyl)-

6;~i8 thien-3-ylmethyl, a-(acetoxymethoxycarbonyl)-thien-2-ylmethyl, a-(benzyloxycarbonyl)benzyl, a-(4-nitrobenzyloxy-carbonyl)benzyl, a-(4-methoxybenzyloxycarbonyl)benzyl, a~(2,2,2-trichloroethoxycarbonyl)benzyl, a-(_-chlorophen-acyloxycarbonyl)-4-bromobenzyl, a-(benzyloxycarbonyl)-3-chlorobenzyl, a- (4-nitrobenzyloxycarbonyl)-4-fluorobenzyl, a- (4-nitrobenzyloxycarbonyl)-3-methoxybenzyl, a-(4-methoxy-benzyloxycarbonyl)-~-isopropoxybenzyl, a-benzyloxycarbonyl-3-nitrobenzyl, a- (4-nitrobenzyloxycarbonyl)-2-cyanobenzyl, a~ bromophenacyloxycarbonyl)-4-trifluoromethylbenzyl, a- (4-nitrobenzyloxycarbonyl)-4-methylbenzyl, ~-benzyloxy-carbonyl-3-_-butylbenzyl, a-(benzyloxycarbonyl)-4-methoxy-:::: .:.:benzyl, ~-(~-nitrobenzyloxycarbonyl)-3-isopropoxybenzyl, thien-2-ylmethyl, thien-3-ylmethyl, fur-2-ylmethyl, fur-3-ylmethyl, thiazol-2-ylmethyl, tetrazol-5-ylmethyl, tetra201 ; -l-ylmethyl, isoxazol-4-ylmethyl and 3-(2-chlorophenyl)-5-methylisoxazol-4-yl.
In portions of the definition of this invention, -~
the group -COORl appears. This represents a "protected carboxy" group.
The term "protected carboxy" refers to a carboxy group which has been protected by one of the commonly used carboxylic acid protecting groups employed to block or protect the carboxylic acid functionality of a compound while a reaction or sequence of reactions involving other functional sites of the compound are carried out. Such protected carboxy groups are noted for their ease of cleavage to the corresponding carboxylic acid by hydrogenolytic methods. Examples of carboxylic acid protecting groups -' '' ' ' .' ' ,' ~', . '' .

.:
.,. ,., . , ''. : .

, . ... .

include benzyl, 4-methoxybenzyl, C2-C6 alkanoyloxymethyl, 4-nitrobenzyl, phenacyl, _-halophenacyl, dimethylallyl, 2,2,2-trichloroethyl and succinimidomethyl. The nature of such ester forming groups is not critical so long as the ester formed therewith is stable under the reaction condi-tions of the process of this invention. Furthermore, other -~
known carboxy protecting groups such as those described by E. Haslam in Protective Grou~ in Organic Chemistry, Chapter 5, are considered to be within the term "protected carboxy" as used herein.
Preferred Rl groups which participate in the overall definition of th~ term "protected carboxy" are benzyl, 4-methoxybenzyl, 4-nitrobenzyl, 2,2,2-trichloro-ethyl, phenacyl, and p-halophenacyl.
In the foregoing discussion, carboxy protecting groups, of course, are not exhaustively described. The function of these groups is to protect reactive functional groups during preparation of a desired product. They then .
can be removed without disruption of the remainder of the molecule. Many such protecting groups are well known in the art, and their use is equally applicable in the process of this invention.
The process of this invention also can be carried out using 3-exomethylenecepham sulfoxides of Formula II
in which R is a cyclic imido group of the formula ~ ~' ' ' .
R2 ~N--~ , , ~-4560 -9-~66Z68 This cyclic imido group, defined by R2 taken together with the nitrogen-carbonyl combination to which it is bonded, can be formed by reacting the 7-amino group of a

7-amino-3-exomethylenecepham ester with a dicarboxylic acid or anhydride or other reactive variant thereof, followed by reacting the resulting derivative with a Cl to C4 alkyl haloformate, for example, ethyl chloroformate, in the presence of an organic base. R2 is C2-C4 alkenylene or 1,2-phenylene and can be considered as being the residue of a dicarboxylic acid, the cyclic imide thus represented being prepared from such dicarboxylic acid, its anhydride, or an appropriate reactive variant thereof. Cyclic imides can be prepared, for example, from acids such as maleic, methyl-maleic and phthalic, or their respective anhydrides, as well as related compounds and compounds of similar reactiv-ities. Additional examples of cyclic anhydrides of the type defined are found in the prior art, such as in the Journal of Organic Chemistry, Volume 26, pp. 3365-3367 (September, 1961).
In addition, the group R in Formulae I and II
can be an imidazolidinyl group of the formula CH~ ~
H3 - . : . . .
in which U i5 nitroso or acetyl and R' is phenyl or phenyl substituted with 1 or 2 halogens, nitro, cyano, trifluoro- ;
methyl, Cl-C4 alkyl, or Cl-C4 alkoxy.

. . .

,: . ' ' ' , . ' - ~ ' '. .': , ' ~, , , ', ' ' ' ' ' ' ' ' ' :
:-' ., . ' .' ', ' ~ , , ' ', ', ' :' ' ', ,,'' ;, ,, ' ': , .. . . . . . . . . . . . . .
, ' , . .. .

~06626~3 The group thus represented is a 2,2-dimethyl-3-nitroso-5-oxo-4-(substituted)-imidazolidin-l-yl group or a 2,2-dimethyl-3-acetyl-5-oxo-4-(substituted)-imidazolidin- :
l-yl group, and the 4-substituent (R') in the imidazolidinyl formula typically includes phenyl, 3-bromophenyl, 2-chlorophenyl, 4-~luorophenyl, 3-iodophenyl, 3-chloro-4-fluorophenyl, 2-chloro-4-bromophenyl, 4-nitrophenyl, 2-cyanophenyl, 3-trifluoromethylphenyl, 4-methylphenyl, 3-ethylphenyl, 4-isopropylphenyl, 4-t-butylphenyl, 3-methoxy-phenyl, 2-ethoxyphenyl, 4-_-propoxyphenyl, 3-isopropoxy-phenyl or 4-isobutoxyphenyl.
The 3-exomethylenecepham sulfoxide starting materials of Formula II in which R is the aforedescribed imidazolidinyl group can be prepared in accordance with known techniques by reacting an exomethylenecepham of the formula t NH~ 0~ CH2 ~OORl or its corresponding free acid with acetone under moderately basic conditions to produce the labile intermediate of the formula R

C~,~
~OOR

X-4560 -ll-~662~3 This product then is converted to the stable N-nitroso or N-acetyl derivative in which R is the aforedescribed imi-dazolidinyl group by treating the product with sodium nitrite or acetic anhydride under acidic conditions and with cooling. The resulting product then can be oxidized to the corresponding sulfoxide of Formula II by well recognized techniques. These preparations are detailed in Gottstein et al., J. O~. Chem., 37 (1972) 2765; and Heusler, Helvetica Chimica Acta, 55 (1972) 388. ~-~
AS will be apparent to those of ordinary skill in -the penicillin and cephalosporin arts, any of the 3-exo-methylenecepham sulfoxide starting materials of Formula II
are readily preparable ~rom available penicillin sources, such as naturally occurring Penicillin G and/or Penicillin V.
6-Aminopenicillanic acid (6-APA) can be prepared from either of the above naturally-occurring penicillins by cleavage of the 6-acyl function employing techniques well known in the art.
It is possible to prepare, by widely recognized techniques and from 6-APA, any of the starting materials of Formula II. For example, 6-APA can be converted to the desired ester by esterification of the 3-carboxyl function - employing any of several typical esterification techniques.
Furthermore, the amino group of 6-APA can be acylated to produce any of the groups defined herein by the term R. This is achieved by reacting 6-APA with an acti- ;
vated form o~ the acid of the intended acyl group. Such activated forms include the corresponding acid halides, anhydrides, or activated esters~, such as the pentachloro-phenyl ester.

: . :
' .' . :'' " ~

Likewise, the penicillin can be oxidized to the sulfoxide under any of a wide variety of recognized con-ditions, including treatment of the penicillin with m-chloroperbenzoic acid or sodium periodate.
These conve~sions, cleavage to 6-APA, esterifica-tion, acylation, and oxidation, can be carried out in any sequence consistent with the intended structural modifi-cations. In any event, all such conversions can be accom-plished employing techniques, conditions, and reagents ~ ~-10 readily available to and well recognized by one of ordinary skill in the art.
Once the penicillin sulfoxide ester of the formula O
.
f ~CH3 ---N~ /`C~13 ~OOR1 . ,~
has been obtained, it can be converted to the corresponding 20 3-exomethylenecepham sulfoxide of Formula II by treatment with an N-chloro halogenating agent, for example, N-chloro-succinimide or N-chlorophthalimide, in a dry, inert solvent, for example, 1,1,2-trichloroethane or toluene, at a tem-perature of from about 75C. to about 135C. to provide an azetidinone sulfinyl chloride of the formùla R /~

o~ CH
~OOR

~ "
lL~)662~
The sulfinyl chloride then is reacted with a Lewis acid Friedel-Crafts type catalyst in a dry, inert, organic solvent to effect cyclization and to provide the desired 3-exomethylenecepham sulfoxide ester of Formula II, a ~-starting material of the process of this invention.
Lewis acid Friedel-Crafts catalysts which are useful in the cyclization of the azetidinone sulfinyl chloride include, for example, stannic chloride, zinc chloride, zinc bromide, titanium tetrachloride, and zir-conium chloride. Stannic chloride is the preferred catalystfor cyclization. The cyclization is carried out at a temperature of from about 20C. to about 85C. and in an inert solvent, preferably an aprotic organic solvent, for example, an aromatic hydrocarbon such as benzene, toluene or xylene; or a halogenated aliphatic hydrocarbon such as methylene chloride, 1,2-dichloroethane or 1,1,2-trichloro- ;
ethane.
As an example of the foregoing preparation of a starting material useful in this process, a solution of ~-nitrobenzyl 6-phenoxyacetamidopenicillanate sulfoxide in dry toluene is treated with 1.1 molar equivalents of N-chlorosuccinimide, and the reaction mixture is refluxed for about 90 minutes. The reaction mixture containing p-nitrobenzyl 3-methyl-2-(2-chlorosulfinyl-4-oxo 3-phenoxy-acetamido-l-azetidinyl)-3-butenoate (the sulfinyl chloride intermediate), is cooled to a temperature of about 50C., and l.l molar equivalents of anhydrous stannic chloride are added. The mixture thus obtained is stirred at room tem-perature for about 90 minutes. Water and ethyl acetate are X-4560 -14- ;

' '' , ... . . . . . . .
... . . . ...
-,, ~ ' '.,,, ~ ' .. ' ~ . :
,~ , :

~L~36~Z6~3 added to the reaction mixture, and the organic layer is separated. The organic layer containing the product is -washed with dilute acid, dilute sodium bicarbonate solution, and then with brine. The washed organic layer then is dried and evaporated to yield _-nitrobenzyl 7-phenoxyacetamido-3-exomethylenecepham-4-carboxylate-l-oxide.
Preferred 3-exomethylenecepham sulfoxide esters of Formula II for use as starting materials in the process of this invention are those having the formula o /-=--~ 11 9~ ~19- (O) rn CH2-C-NH~ ~5 ~, ~, t __ ~ ~CH2 in which m is O or l and Rl is a carboxylic acid protecting group.
Correspondlngly, the preferred 3 acyloxymethyl-~ -cephem ester products of Formula I obtained from the process of this invention are those of the formula /o=~ ~
-(o)~c~l2-c-NH\ T/ \~
N\ /~-CH2-O-C-R4 in which m is O or l, Rl is a carboxylic acid protecting group, and R4 is Cl-C4 alkyl, and, more preferably, methyl.
Another class of preferred 3-exomethylenecepham sulfoxide esters of Formula II for use in the process of this invention are those having the formula 1~6Z68 \5/ ~tt/ \l O~ N\ / ~CHZ

in which Rl is a carboxylic acid protecting group.
The 3-acyloxymethyl-~2-cephem esters of Formula I
produced from the aforementioned preferred class have the formula O
ILcH~c-NH /S\ O
N _CHZ-O-C-R4 in which Rl is a carboxylic acid protecting group and R4 is .
Cl-C4 alkyl, and, more preferably, methyl. ~.

', , , , ' ' ' .

--The conversion of the 3-exomethylenecepham sul- -foxide to the corresponding 3-acyloxymethyl-A2-cephem is accomplished by reaction with a mixture of an acyl compound of the formula and a corresponding anhydride of the formula O
(R4-C-)2 IV
in which R4 is Cl-C4 alkyl. ~hus, the acyl compounds which can be employed include, for example, acetic acid, propionic acid, n-butyric acid, isobutyric acid, valeric acid, tri-methylacetic acid, a-methylbutyric acid and ~-methylbutyric acid. As indicated above, each of these acyl compounds is employed in combination with its corresponding symmetrical acid anhydride. For example, when it is intended that the product be a 3 propionoxymethyl-A -cephem ester, a mixture of propionic acid and propionic anhydride, is employed. It is highly preferred, in the process of this invention, ' ' ' ' ' , . ' , ' .

~: :

~L066;Z6~

that a mixture of acetic acid and acetic anhydride be employed, thereby producing, as product, a 3-acetoxymethyl-A2-cephem ester.
In carrying out the process of this invention, the 3-exomethylenecepham sulfoxide is mixed with a mixture of the selected carboxylic acid and its corresponding anhydride.
Generally, the molar ratio of carboxylic acid to anhydride is from about 1:12 to about 35:1, and, preferably,- from ,.-,.,. ~ , ` " ' ..

', -~.~ :~ - .

.
' ', ' ' ' .

about 2:5 to about 7:1. Generally from about 1 to about 40 millimoles of anhydride, and from about 2 to about 65 milli-moles of acid, at least, will be used per each millimole of 3 exomethylenecepham sulfoxide~ A large excess of the acylating mixture can be employed without detriment; how-ever, no advantage is apparent from the use of a vast excess of the acid-anhydride mixture. Preferably, there-fore, the acid-anhydride mixture is present in amounts from about 2 to about 250 millimoles of anhydride, and from about 4 to about 400 millimoles of acid, per each millimole of the 3-exomethylenecepham sulfoxide.

.

, ", , , . , . , : , , . , : , ~066~8 Typically, the 3-exomethylenecepham sulfoxide is added ~o ~he prepared mixture of the acyl compound and its corresponding anhydride. The resulting mixture then is heated at a temperature of from about 70C. to about 130C.
for a time sufficient to achieve conversion to the desired 3-acyloxymethyl-~2-cephem compound of Formula I~ The time necessary to achieve reaction can vary over a wide range, -and, typically, will be from about 2 hours to about 80 hours, and, preferably, from about 4 hours to about 6 hours.
It is possible to employ an inert organic solvent in addition to the acylating mix~ure, particularly when an acyl chloride is used. However, this is not essential, and it does not in any way contribute to the success of the reaction. Examples of inert organic solvents which can be employed include aromatic hydrocarbons, such as benzene, toluene and ethylbenzene; chlorinated hydrocarbons, such as chlorobenzene, carbon tetrachloride and 1,1,2-trichloro-ethane; and esters, such as ethyl acetate, butyl acetate and ethyl propionate.
The resulting 3~acyloxymethyl-a2-cephem product is recovered by evaporation of the excess materials and puri-fication of the resulting residue by employing conventional techniques. Such techniques include, for example, chroma-tographic separation, filtration, crystallization, recrys-tallization, and other such recognized methods.
Examples of conversions which are available in accordance with the process of this invention include:
~-nitrobenzyl 7-maleimido-3-methylenecepham-4-carboxylate-l-oxide to ~-nitrobenzyl 7-maleimido-3-acetoxy-methyl-2-cephem-4-carboxylate;

.

.... . . . . .
. ' ' :::
:, . ~ , ' , . ,, ' , . ' ' ':

~06~;268 2,2,2-trichloroethyl 7-phthalimido-3-methylene-cepham-4-carboxylate-1-oxide to 2,2,2-trichloroethyl 7-phthalimido-3-propionoxymethyl-2-cephem-4-carboxylate;
benzyl 7-formamido-3-methylenecepham-4-carboxy-late-l-oxide to benzyl 7-formamido-3-butyroxymethyl-2-cephem-4-carboxylate;
2,2,2-trichloroethyl 7-acetamido-3-methylene-cepham-4-carboxylate-1-oxide to 2,2,2-trichloroethyl 7-acetamido-3-acetoxymethyl-2-cephem-4-carboxylate;
_-nitrobenzyl 7-butyramido-3-methylenecepham-4-carboxylate-1-oxide to p-nitrobenzyl 7-butyramido-3-acetoxymethyl-2-cephem-4-carboxylate;
~-methoxybenzyl 7-chloroacetamido-3-methylene-cepham-4-carboxylate-1-oxide to ~-methoxybenzyl 7-chloro-acetamido-3-propionoxymethyl-2-cephem-4-carboxylate;
~-nitrobenzyl 7-(4'-nitrobenzyloxycarboxamido)-3-methylenecepham-4-carboxylate-1-oxide to p-nitrobenzyl 7-(4'-nitrobenzyloxycarboxamido)-3-isobutyroxymethyl-2-cephem-4-carboxylate; . ;~
p-chlGrophenacyl 7~benzyloxycarboxamido-3-methylenecepham-4-carboxylate-1-oxide to _-chlorophenacyl 7-benzyloxycarboxamido-3-valeroxymethyl-2-cephem-4-car-boxylate;
succinimidomethyl 7-(benzyloxycarboxamido)-3-methylenecepham-4-carboxylate-1-oxide to succinimidomethyl 7-(benzyloxycarboxami.do)-3-acetoxymethyl-2-cephem-4-car-boxylate;
''' ~' X-4560 -21 ; ~
''' "
~ -:, . , , , . , , . . ~ .;, .: ,, . . , , : . , .
.

~ 66261~
2,2,2-triehloroethyl 7-~2',2',2'-trichloroethoxy- .
earboxamido)-3-methylenecepham-4-carboxylate-1-oxide to 2,2,2-trichloroethyl 7-(2',2',2'-triehloroethoxyearboxamido)-3-propionoxymethyl-2-eephem-4-earboxylate;
acetoxymethyl 7-(4'-methoxybenzyloxycarboxamido)-3-methylenecepham-4-carboxylàte-1-oxide to acetoxymethyl 7-(4'-methoxybenzyloxyearboxamido~-3-acetoxymethyl-2-cephem-4-carboxylate;
. ~ .
benzyl 7-phenoxyacetamido-3-methylenecepham-10 4-carboxylate-1-oxide to benzyl 7-phenoxyacetamido-3- ~:
acetoxymethyl-2-ceph~m-4-carboxylate; .
, :,, .
phthalimidomethyl 7-benzamido-3-methylenecepham- ~.
4-carboxylate-1-oxide to phthalimidomethyl 7-benzamido-3-a-methylbutyroxymethyl-2-cephem-4-carboxylate;
phenacyl 7-(4'-chlorobenzamido)-3-methyleneeepham-4-carboxylate-1-oxide to phenaeyl 7-(4'-chlorobenzamido)- -3-acetoxymethyl-2-eephem-4-carboxylate;
~-chlorophenacyl 7-(3'-bromobenzamido)-3-methyl-enecepham-4-carboxylate-1-oxide to p-chlorophenacyl 7-(3'-bromobenzamido)-3-aeetoxymethyl-2-cephem-4-earboxylate;
pivaloyloxymethyl 7-(4'-nitrobenzamido)-3-methylenecepham-4-earboxylate-1-oxide to pivaloyloxymethyl 7-(4'-nitrobenzamido)-3-propionoxymethyl-2-cephem-4-carboxylate; :.
acetoxymethyl 7-(2'-cyanobenzamido)-3-methylene-cepham-4-carboxylate-1-oxide to acetoxymethyl 7-(2'-cyano-benzamido)-3-acetoxymethyl-2-cephem-4-earboxylate;
! ~
. ~ '' ', ' ' X-4560 -22- ~

' . , .

.: ~ . , . . , . . ; :, .
' ' :, ' : ' ' ~ : ' ' , ~ :. .: ,' -, . . . . . . .
, . . . . .. .

1~66268 succinimidomethyl 7-(4'-trifluoromethylbenz-amido)-3-methylenecepham-4-carboxylate-1-oxide to suc-cinimidomethyl 7-~4'-trifluoromethylbenzamido)-3-B-methyl-blltyroxymethyl-2-cephem-4-carboxylate;
phthalimidomethyl 7-(3'-methylbenzamido)-3-methylenecepham-4-carboxylate-1-oxide to phthalimidomethyl 7--(3'-methylbenzamido)-3-acetoxymethyl-2-cephem-4-carboxylate;
2,2,2-tribromoethyl 7-(2'-methoxybenzamido)-3-methylenecepham-4-carboxylate-1-oxide to 2,2,2-tribromoethyl 7-(2'-methoxybenzamido)-3-valeroxymethyl-2-eephem-4-carboxylate;
propionoxymethyl 7-phenylacetamido-3-methylene-eepham-4-carboxylate-1-oxide to propionoxymethyl 7-phenyl-acetamido-3-acetoxymethyl-2-cephem-4-carboxylate;
~ -nitrobenzyl 7-(2'-thienylacetamido)-3-methylene-eepham-4-earboxylate-1-oxide to _-nitrobenzyl 7-(21-thienylacetamido)-3-propionoxymethyl-2-cephem-4-carboxylate;
~ -methoxybenzyl 7-phenylacetamido-3-methylene-cepham-4-carboxylate-1-oxide to _-methoxybenzyl 7-phenyl-aeetamido-3-butyroxymethyl-2-cephem-4-carboxylate;
2,2,2-triehloroethyl 7-phenoxyacetamido-3- ~ .
methylenecepham-4-carboxylate-1-oxi.de to 2,2,2-trichloro- -ethyl 7-phenoxyaeetamido-3-aeetoxymethyl-2-eephem-4-.;
carboxylate;
_-nitrobenzyl 7-(2',5'-dichlorophenylacetamido)- .
3-methylenecepham-4-carboxylake-1-oxide to _-nitrobenzyl 7-(2',5'-dichlorophenylacetamido)-3-aeetoxymethyl-2- ~ :
eephem-4-carboxylate;

.. ~ ,., . .: . . . . ... . ......... . .
.: : ' . - , ~ . -.

~0~6'~6~ ~ ~
benzyl 7-(3'-bromophenoxyacetamido)-3 methylene-cepham-4-carboxylate-1-oxide to benzyl 7-(3'-bromophenoxy- -acetamido)-3-isobutyroxymethyl-2-cephem-4-carboxylate; ~:
~-bromophenacyl 7-(4'-chlorophenylacetamido)-3-methylenecepham-4-carboxylate-1-oxide to p-bromophenacyl ~.
7-(4'-chlorophenylacetamido)-3-acetoxymethyl-2-cephem-4- ~ :
carboxylate; :.
pivaloyloxymethyl 7-(3'-chlorophenoxyacetamido)-3~methylenecepham-4-carboxylate~l-oxide to pivaloyloxymethyl 7-(3'-chlorophenoxyacetamido)-3-acetoxymethyl-2-cephem-4-carboxylate; ~.
p-nitrobenzyl 7-(4'-nitrophenylacetamido)-3-methylenecepham-4-carboxylate-1-oxide to p-nitrobenzyl 7-(4'-nitrophenylacetamido)-3-propionoxymethyl-2-cephem-4-carboxylate;
_-methoxybenzyl 7-(4'-nitrophenoxyacetamido)-3-methylenecepham-4-carboxylate-1-oxide to _-methoxybenzyl 7-(4'-nitrophenoxyacetamido)-3-acetoxymethyl-2-cephem-4-carboxylate; .
_-nitrobenzyl 7-(3'-cyanophenylacetamido)-3-methylenecepham-4-carboxylate-1-oxide to -nitrobenzyl 7-(3'-cyanophenylacetamido)-3-butyroxymethyl-2-cephem-4-carboxylate;
p-bromophenacyl 7-(2'-cyanophenoxyacetamido)-3-methylenecepham-4-carboxylate-1-oxide to _-bromophenacyl 7-(2'-cyanophenoxyacetamido)-3-acetoxymethyl-2-cephem- :~
4-carboxylate;

. ' ~' . .
.- : . . . . .
.. . . . .
. .
,, :. .. . . .

~0t;6Z6!3 propionoxymethyl 7-(4'-trifluoromethylphenyl-acetamido)-3-methylenecepham~4-carboxylate-1-oxide to propionoxymethyl 7-(4'-trifluoromethylphenylacetamido)-3-acetoxymethyl-2 cephem-4-carboxylate;
2,2,2-tribromomethyl 7-(3'-trifluoromethylphenoxy-acetamido)-3-methylenecepham-4-carboxylate-1-oxide to 2,2,2-tribromomethyl 7-(3'-trifluoromethylphenoxyacetamido)-3-propionoxymethyl-2-cephem-4-carboxylate;
2,2,2-trichloroethyl 7-~2'-ethylphenylacetamido)-3-methylenecepham-4-carboxylate-1-oxide to 2,2,2-trichloro-ethyl 7-(2'-ethylphenylacetamido)-3-acetoxymethyl-2-cephem-4-carboxylate;
acetoxymethyl 7-(4'-isopropylphenoxyacetamido)-3-methylenecepham-4-carboxylate-1-oxide to acetoxymethyl 7-(4'-isopropylphenoxyacetamido)-3-butyroxymethyl-2- ~-cephem-4-carboxylate;
benzyl 7-(3'-ethoxyphenylac2tamido)-3-methylene-cepham-4-carboxylate~l-oxide to ben~yl 7-(3'-ethoxyphenyl- :
acetamido)-3-isobutyroxymethyl-2-cephem-4-carboxylate; :
_-nitrobenzyl 7-(4'-isopropoxyphenoxyacetamido)- ;
3-methylenecepham-4-carboxylate-1-oxide to _-nitrobenzyl :
7-(4'-isopropoxyphenoxyacetamido)-3 valeroxymethyl-2-cephem-4-carboxylate; ::
~-nitrobenzyl 7-(a-2,2,2-trichloroetho~ycaxbonyl-phenylacetamido)-3-methylenec~pham-4-carboxylate-1-oxide to p-nitrobenzyl 7-(a-2,2,2-trichloroethoxycarbonylphenyl-acetamido)-3-a-methylbutyroxymethyl-2-cephem-4-carboxylate;

. .
:' :,: ' ,'' '',' " " ' ,"'' ' ', ;' ,'', ' ,' ' ,~ . ,'; ' ' ' "' ' , ' ' '' ~ :' , ' ' ' ' ' ' : . ' :. .

- " :
Z68 ~ ~
_-methoxybenzyl 7-~a-phenacyloxycarbonylphenyl- ~-acetamido)-3-methylenecepham-4-carboxylate-1-oxide to _-methoxybenzyl 7-(a-phenacyloxycarbonylphenylacetamido)-3-acetoxymethyl-2-cephem-4-carboxylate;
benzyl 7-(2-thienyl-a-benzyloxycarbonylacetamido)-3-methylenecepham-4-carboxylate-1-oxide to benzyl 7-(2-thienyl-a-benzyloxycarbonylacetamido)-3-~-methylbutyroxy-methyl-2-cephem-4-carboxylate;
2,2,2-trichloroethyl 7-(a-p~nitrobenzyloxycar-bonylphenylacetamido)-3-methylenecepham-4-carboxylate-1-oxide to 2,2,2-trichloroethyl 7-(a-~-nitrobenzyloxycarbonyl-phenylacetamido)-3-acetoxymethyl-2-cephem-4-carboxylate;
_-nitrobenzyl 7-(a-benzyloxycarbonylphenylacet-amido)-3-methylenecepham-4-carboxylate-1-oxide to ~-nitro-benzyl 7-(a-benzyloxycarbonylphenylacetamido)-3-acetoxy-: methyl-2-cephem-4-carboxylate;
p-methoxybenzyl 7-(a-4-methoxybenzyloxycarbonyl-phenylacetamido)-3-methylenecepham-4-carboxylate-1-oxide to : .
~-methoxybenzyl 7-(a-4-methoxybenzyloxycarbonylphenylacet-amido)-3-propionoxymethyl-2-cephem-4-carboxylate;
_-nitrobenzyl 7 (2'-thienyl-a-~-nitrobenzyloxy-carbonylacetamido)-3-methylenecepham-4-carboxylate-1-oxide ~:
to _-nitrobenzyl 7-(2'-thienyl-a-~-nitrobenzyloxycarbonyl-acetamido)-3-acetoxymethyl-2-cephem-4-carboxylate;
_-nitrobenzyl 7-(2'-thienylacetamido)-3-methylene-cepham-4-carboxylate-1-oxide to ~-nitrobenzyl 7-(2'-thienylacetamido)-3-acetoxymethyl-2-cephem-4-carboxylate;

~0662~;13 benzyl 7-(3'~thienylacetamldo)-3-methylenecepham-4-carboxylate-1-oxide to benzyl 7-(3'-thienylacetamido)-3-acetoxymethyl-2-cephem-4-carboxylate;
_-methoxybenzyl 7-(2'-furylacetamido)-3-methylene-cepham-4-carboxylate-1-oxide to _-methoxybenzyl 7-(2'-~urylacetamido)-3-propionoxymethyl-2-cephem-4-carboxylate;
_-chlorophenacyl 7-(3'-furylacetamido)-3~methyl-enecepham-4-carboxylate-1-oxide to _-chlorophenacyl 7-(3'-furylacetamido~-3-butyroxymethyl-2-cephem-4-carboxylate;
succinimidomethyl 7-(2'-thiazolylacetamido~-3-methylenecepham-4-carboxylate-1-oxide to succinimidomethyl 7-(2'-thiazolylacetamido)-3-valeroxymethyl-2-cephem-4-carboxylate;
~-nitrobenzyl 7-(5'-tetrazolylacetamido)-3-methylenecepham-4-carboxylate-1-oxide to p-nitrobenzyl :
7-(5'-tetrazolylacetamido)-3-~-methylbutyroxymethyl-2- ~:
cephem-4-carboxylate;
p-nitrobenzyl 7-(1'-tetrazolylacetamido)-3-methylenecepham-4-carboxylate-1-oxide to _-nitrobenzyl 7-(1'-tetrazolylacetamido)-3-acetoxymethyl-2~cephem-4-carboxylate;
_-methoxybenzyl 7-(4'-isoxazolylacetamido)-3-methylenecepham-4-carboxylate-1-oxide to ~-methoxybenzyl .:
7-(4'-isoxazolylacetamido)-3-acetoxymethyl-2-cephem-4-carboxylate;
benzyl 7-[3'-(2"-chlorophenyl)-5'-methylisoxazol-4'-ylcarboxamido]-3-methylenecepham-4-carboxylate-1-oxide to benzyl 7-[3'-(2"-chlorophenyl)-5'-methylisoxazol-4'-ylcarboxamido]-3-~-methylbutyroxymethyl-2-cephem-4-car-30 boxylate; ~:

:. , , . , , "
. , , ' . , , , ,, ' :, , ' . . ', :
-' ' ' , ,' , : , , . ,, ', , ~ ' :
, , - , ; :: :
.. . . ... . .. . . .

~6~26~3 _-nitrobenzyl 7-(2',2'-dimethyl-3'-acetyl-5'-oxo-4'-phenylimidazolidin-1'-yl)-3-methylenecepham-4-carboxylate-l-oxide to _-nitrobenzyl 7-(2',2'-dimethyl-3'-acetyl-5'-oxo-4'-phenylimidaæolidin-1'-yl)-3-acetoxymethyl 2~cephem-4-carboxylate;
benzyl 7-[2',2'-dimethyl-3'-nitroso-5'-oxo-4'-(4"-chlorophenyl)imidazolidin-1'-yl]-3-methylenecepham-4--carboxylate-1-oxide to benzyl 7-[2',2'-dimethyl-3'-nitroso-5'-oxo-4'-(4"-chlorophenyl)imidazolidin-1'-yl]-3-acetoxymethyl-2-cephem-4-carboxylate.
The 3-acyloxymethyl-~2-cephem esters of Formula I
are useful as intermediates in the preparation of anti-biotically active cephalosporins. The A2-cephem product is treated in accordance with the method described in U.S.
Patent No. 3,705,897 to produce the corresponding ~3-cephem ester. The described method, although specifically directed to 3-halomethyl-~2-cephem compounds, nevertheless, is fully applicable to the 3-acyloxymethyl-Q2-cephem esters oE Formula I. The method which is described in the U.S.
patent involves oxidation of the ~2-cephem compound using an oxidizing agent to produce a cephem sulfoxide. With respect to at least a portion of the oxidized product, isomerization oP the double bond from the ~2 position to the ~3 position occurs. Isomerization of the double bond of the sulfoxide is completed by treating the product with a tertiary amine.
The resulting ~3-cephem sulfoxide is reduced to the corre-sponding sulfide by treatment with any of a number of defined reducing agents. When this method is applied to the ;
products of Formula I from the process of this invention, a 3-acyloxymethyl-~3-cephem ester is obtained.

., , .

~L0g~6Z6~
At this point, it is noteworthy to recognize that, in addition to the a2-cephem product of Formula I obtained from the process of this invention, a minor amount of the corresponding A3-cephem compound generally will be produced.
The two products, of course, can be separated using one or more of any of several readily recognized techniques, such as those described above. However, since the customary purpose for generating the a2-cephem compound will con-template its ultimate conversion to a Q3-cephem antibiot-ically active compound, no separation is necessary. Themixture of the a2-cephem and the Q3-cephem, as obtained frcm the process of the invention, can be treated, under the conditions described above, to produce the desired ~3-cephem compound. The a3-cephem present in the starting material as contaminant will simply be oxidized to the sulfoxide and reduced back to the sulfide, and thus be recovered as the desired product. ~ -~
The corresponding a3-cephem acids exhibit potent antibacterial activity. Such compounds are available by cleavage of the ester function. De-esterification can be achieved, depending upon the nature of the protecting group, by any of several recognized procedures, including (1) treatment with an acid such as trifluoroacetic acid, formic acid or hydrochloric acid; (2~ treatment with zinc and an acid such as formic acid, acetic acid, or hydrochloric acid;
or (3) hydrogenation in the presence of palladium, platinum, rhodium, or a compound thereof, in suspension, or on a carrier such as barium sulfate, carbon or alumina. Further-more, the resulting 3-acyloxymethyl-a3--cephem acid is X-45~0 ~29- -., " ,. ,, ., : . ' ' .
:, . , .. - . , . , . . , :
.'' . ' , . . '.:, ' ,. , ' .. . :,' '',: .
: . , ,, . .... ~ '' ., :. ... :

~066Z68 convertible to-other antibiotlcally active cephalosporins by cleavage of the amido or imido group in the 7-position to the free 7-amino group with subsequent reacylation to produce any of a number of recognized active cephalosporin antibiotics. Cleavage and reacylation methods are well recognized in the cephalosporin art.
By the process of this invention, therefore, -several widely recognized cephalosporin antibiotics are available. These include, for example, the sodium salt of 7-(2-thienylacetamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid (cephalothin); 7-(-aminophenylacetamido)-3-acetoxy-methyl-3-cephem-4-carboxylic acid (cephaloglycin); and the sodium salt of 7-cyanoacetamido-3-acetoxymethyl-3-cephem-4-carboxylic acid (cephacetrile).
This invention is further illustrated by the examples which follow. It is not intended that this inven-; tion be limlted in scope by reason of any of the examples provided herein. Preparations showing the use of the com-pounds of Formula I are also provided.

, `: `
~L~G6%68 Example 1 To a mixture of 33 ml. of acetic acid and 66 ml. -~
of acetic anhydride were added 6 gms. (12 mmoles) of p-nitrobenzyl 7-phenoxyacetamido-3~methylenecepham-4-car-boxylate-l-oxide. The mixture was maintained under a slow stream of nitrogen and then was brought to reflux (about 126C.). Progress of the reaction wa~ followed by thin-layer chromatography (TLC) using a 1:1 mixture of benzene and ethyl acetate on silica gel plates. The reaction was 10 complete in about 2.5 hours, after which time the resulting - -reddish solution was evaporated to a dark tar. The resulting residue was dissolved in 50 ml. of ethyl acetate. The ethyl acetate solution was washed three times with 50 ml. each o~
saturated sodium bicarbonate solution and once with 50 ml. -of saturated sodium chloride solution. The ethyl acetate -layer then was dried over magnesium sulfate, treated with activated carbon, and filtered through silica gel. The filtrate was evaporated to obtain 5.8 gms. (89 percent) of a 3:1 mixture of _-nitrobenzyl 7-phenoxyacetamido-3-acetoxy-methyl-2-cephem-4-carboxylate and ~-nitrobenzyl 7-phenoxy-acetamido-3-acetoxymethyl-3-cephem-4-carboxylate as a light yellow foam.
nmr (3:1 mixture of Q and ~3) ~ (CDC13) 6.5 (broad s, 0.75, ~2-C2); 5.8 (dd, 1, C7-H); 4.6 (s, 2, C
methylene); 3.6 (broad s, 0.5, ~3-C2); and 2.1-2.2 (ss, 3 ~2 and ~3 C3, acetoxy)-Examples 2-6 The reaction of Example 1 was repeated under varying conditions as follows:

' , .'' . ,. , ' ' . ' ', ' . ' ..'' :, ' ,' "
. , ' , ~ , , j, . .

~66Z68 ~, . ~ : .
~ e ~
O tJ~
~4 :
:
. .. -' G) u~ ul :, e ~ In r~.l ~1 ~
E~ .' e o u~ co u~r ,, -o t) .~ ~
U U E~ ~D O OUl O ,.

a) u ~
~ ~ u~ o u~ o ~ e :
a) ~ :
.
x u~
O E~
~J
o X-4560 -32~

~L06626~3 Example 7 --.:
To a mixture of 5 ml. of acetic anhydride and 20 ml. of acetic acid were added 600 mg. oE 2,2,2-trichloro-ethyl 7-(p-nitrobenzyloxycarbonylamino)-3-methylenecepham-4~carboxylate-l-oxide. The resulting mixture was stirred at 110C. for six hours. The reaction mixture then was cooled, and the solvent was evaporated. The resulting residue was dissolved in ethyl acetate, and the ethyl acetate solution was washed with saturated aqueous sodil~ bicarbonate. The organic layer then was dried over magnesium sulfate, evap-orated, and the residue was chromatographed over silica gel to obtain 100 mg. of a 6:1 mixture of 2,2,2-trichloroethyl 7 (p-nitrobenzyloxycarbonylamino)-3-acetoxymethyl-2-cephem-4-carboxylate and 2,2,2-trichloroethyl 7-(p-nitrobenzyloxy- -carbonylamino)-3-acetoxymethyl-3-cephem-4-carboxylate.
nmr (6:1 mixture of ~ and ~ ) ~ (CDCl3) 6.45 (broad s, 0.83, ~ -C2); 4.75 ~s, 2, trichloroethyl); 4.65 (broad s, 1.66, A C3'-methylene); 3.5 (broad s, 0.34, -~3 C2); and 2.10-2.15 (broad s, 3, ~2 and ~3 C3'-acetoxy).
Example 8 To a mixture of 5 ml. of acetic anhydride and 20 ml. of acetic acid were added 600 mg. of ~-nitrobenzyl 7-(2-thienylacetamido)-3 methylenecepham-4-carboxylate-l-oxide. The resulting mixture was stirred at 110C. for four hours. The mixture was cooled, evaporated, and the resulting residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with aqueous sodium bicarbonate and dried over magnesium sulfate. The solvent was evap-orated, and the residue was chromatographed over silica gel ' " -, ' : ;' ' ' ' ' ', ' ,: ' : , . ,' ., . ' ' , . , :

~06~;Z6~
to obtain 110 mg. of p-nitrobenzyl 7-(2-thienylacetamido)-3~acetoxymethyl-2-cephem-4-carboxylate. -nmr ~ (CDC13) 6.4 (broad s, 1, ~ -C2); 5.6 (dd, 1, C7-H); 4.6 (broad s, 2, C3'-methylene); 3.8 (s, 2, C7-methylene); and 2.05 (s, 3, C3'-acetoxy).
Example 9 To a mixture of 5 ml. of propionic anhydride and 20 ml. of propionic acid were added 600 mg. of _-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate-1-oxide.
The mixture was stirred at 130C. for six hours. The resulting mixture was cooled, and the solvent was removed in vacuo. The resulting residue was dissolved in 150 ml. of -ethyl acetate, and the ethyl acetate solution was washed with saturated aqueous sodium bicarbonate. The ethyl ~acetate layer was separated and dried over magnesium sul-fate.- The solvent was evaporated, and the residue was chromatographed on silica gel to obtain 166 mg. of ~-nitro-benzyl 7-phenoxyacetamido-3-propionyloxymethyl-2-cephem-4-carboxylate.
nmr ~ (CDC13) 6.4S (broad s, 1, ~2-C2); 5.7 (dd, 1, C7-H); 2.3 (q, 2, methylene of propionoxy); and 1.1 (t, 3, methyl of propionoxy).
Example 10 To a mixture of acetic anhydride and acetic acid was added a portion of p-nitrobenzyl 7-phenylacetamido-3-.

10~6;~6~3 methylenecepham-4-carboxylate-1-oxide. The mixture was : .
heated and stirred for a time, and was then cooled and evaporated to dryness. The residue was dissolved in ethyl acetate, and the product was purified as described in the examples above to obtain p-nitrobenzyl 7-phenyl-acetamido-3-acetoxymethyl-2-cephem-4-carboxylate.

.' ' .
, - ~ -~IL066Z~8 Preparation 1 -To 170 ml. of methylene chloride were added 5~65 gms. o~ _-nitrobenzyl 7-phenoxyacetamido-3-acetoxy-methyl-2-cephem-4-carboxylate and 20 ml. of isopropyl alcohol. The mixture was cooled to about 0C. A solution of 2.12 gms. of 85 percent technical grade _-chloroper-benzoic acid in 55 ml. of methylene chloride was added ,~
dropwise rapidly. The progress of the reaction was followed by TLC. After 45 minutes, the methylene chloride mixture was washed three times with 100 ml. of aqueous sodiumchloride solution~ The methylene chloride layer then was dried over magnesium sulfate and tre-ated with activated carbon. The methylene chloride solution then was cooled in an ice bath, and petroleum ether was added slowly to obtain, by crystallization, 4.39 gms. (76 percent) of p-nitrobenzyl 7-phenoxyacetamido-3-acetoxymethyl-3-cephem-4-carboxylate-l-oxide, m.p. 187-188C.
Analysis: Calc. for C25H23N3OloS
Theoretical Found C 53.86% 53.67%
~ 4.16 3.~39 N 7.54 7.29 O 28.70 28.45 S 5.75 5.38 Preparation 2 To 75 ml. of N,N-dimethylformamide (DMF) were added 2.70 gms. of the product from Preparation 1. The mixture was cooled to -80C., and 1.6 ml. oE phosphorous trichloride was added in one portion. The resulting mixture ~L066Z68 .
was stirred for 10 mlnutes at -80C., a-nd then was warmed to about 0C. using an ice water bath. Stirring of the mixture was continued for about 25 minutes, and the resulting orange solution then was poured onto ice. A precipitate-formed and was removed by filtration, washed thoroughly with water, and dried to give 2.35 gms. (8905 percent-~ of ~-nitrobenzyl 7-phenoxyacetamido-3-acetoxymethyl-3-cephem-4-carboxylate.
nmr ~ (CDC13-DMSO 1:1) 2.03 (s, 3H, acetoxy);
3.50 (6s, 2H, -S-CH2-); 4.53 (s, 2H, -O-CH2-NH-); 4.90 (d, lH, J = 4.5 Hz, C6-H); 5.90 (d, lH, J = 4.5 Hz), C7-H);
5.20, 5~30 (2s, lH + lH, acetoxymethyl); 5.33 (s, 2H, -nitrobenzyl); 6.77-7.40 (m, 5H, phenoxy); 7.53, 8.17 (2d, 2H + 2H, AB, J = 9 Hæ, nit~obenzylcarboxylate).

~, . .... . . . .
.
" ' , : '

Claims (16)

The embodiments of the invention for which an exclusive property or privilege is claimed are as follows:

1. A process for preparing a compound of the formula I

which comprises reacting a 3-exomethylenecepham sulfoxide of the formula II

with a mixture of an acyl compound of the formula III
and a corresponding anhydride of the formula IV

at a temperature of from about 70°C. to about 130°C., in which, in the above formulae, R4 is C1-C4 alkyl, R1 is a carboxylic acid protecting group, and R is (1) an imido group of the formula in which R2 is C2-C4 alkenylene or 1,2-phenylene;
(2) an amido group of the formula R3-?-NH-in which R3 is (a) hydrogen, C1-C3 alkyl, halomethyl, benzyloxy, 4-nitrobenzyloxy, 2,2,2-trichloroethoxy, 4-methoxybenzyloxy, or 3-(2-chlorophenyl)-5-methylisoxazol-4-yl;
(b) the group R' in which R' is phenyl or phenyl substituted with 1 or 2 halogens, nitro, cyano, trifluoro-methyl, C1-C4 alkyl, or C1-C4 alkoxy;
(c) a group of the formula R'-(O)m-CH2- in which R' is as defined above and m is 0 or 1;
(d) a group of the formula in which R" is R' as defined above, 2-thienyl, or 3-thienyl, and R1 is as defined above; or (e) a group of the formula R'''-CH2- in which R"' is 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-thiazolyl, 5-tetrazolyl, 1-tetrazolyl, or 4-isoxazolyl; or R is (3) an imidazolidinyl group of the formula in which R' is as defined above and U is nitroso or acetyl.

2. The process of claim 1, in which R is a group of the formula R'-(O)m-CH2-?-NH-.

3 The process of claim 2, in which R1 is phenyl.

4. The process of claim 2 or 3, in which m is 0.

5. The process of claim 2 or 3, in which m is 1.

6. The process of claim 1 in which R is a group of the formula R'''-CH2-?-NH-.

7. The process of claim 6, in which R''' is 2-thienyl.

8. The process of claim 1 in which R1 is 2,2,2-trihalo-ethyl, benzyl, p-nitrobenzyl, succinimidomethyl, phthalimidomethyl, p-methoxybenzyl, C2-C6 alkanoyloxymethyl, dimethylallyl, phenacyl, or p-halophenacyl.

9. The process of claim 8, in which R1 is benzyl, p-nitrobenzyl, p-methoxybenzyl, 2,2,2-trichloroethyl, phenacyl, p-chlorophenacyl, or p-bromophenacyl.

10. The process of claim 1 in which R4-?-OH is acetic acid.

11. The process of claim 1 in which the anhydride is present in an amount representing at least about a molar equivalent relative to the 3-exomethylenecepham sulfoxide.

12. A process of Claim 1 for preparing p-nitro-benzyl 7-phenoxyacetamido-3-acetoxymethyl-2-cephem-4-car-boxylate which comprises reacting p-nitrobenzyl 7-phenoxy-acetamido-3-methylenecepham-4-carboxylate-1-oxide with acetic acid and acetic anhydride.

13. A process of Claim 1 for preparing 2,2,2-trichloroethyl 7-(p-nitrobenzyloxycarbonylamino)-3-acetoxy methyl-2-cephem-4 carboxylate which comprises reacting 2,2,2-trichloroethyl 7-(p-nitrobenzyloxycarbonylamino)-3-methylenecepham-4-carboxylate-1-oxide with acetic anhydride and acetic acid.

14. A process of Claim 1 for preparing p-nitro-benzyl 7-(2-thienylacetamido)-3-acetoxymethyl-2-cephem-4-carboxylate which comprises reacting p-nitrobenzyl 7-(2-thienylacetamido)-3-methylenecepham-4-carboxylate-1-oxide with acetic anhydride and acetic acid.

15. A process of Claim 1 for preparing p-nitro-benzyl 7-phenoxyacetamido-3-propionyloxymethyl-2-cephem-4-carboxylate which comprises reacting p-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate-1-oxide with propionic anhydride and propionic acid.

16. A process of Claim 1 for preparing p-nitro-benzyl 7-phenylacetamido-3-acetoxymethyl-2-cephem-4-car-boxylate which comprises reacting p-nitrobenzyl 7-phenyl-acetamido-3-methylenecepham-4-carboxylate-1-oxide with acetic anhydride and acetic acid.